Method of treating hemorrhagic conditions

ABSTRACT

THE COMPOUND 4-(A-AMINO LOWEER ALKYL)BICYCLO-(2,2,2)OCTAN-1-CARBOXYLIC ACID AND THE PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF ARE USEFUL AS ANTI-FIBRINOLYTIC COMPOUNDS.

United States Patent 3,767,814 METHOD OF TREATING HEMORRHAGIC CONDITIONS Larry J. Loefller, North Wales, Pa., assignor to Merck & Co., Inc., Rahway, NJ.

No Drawing. Original application June 17, 1969, Ser. No. 834,138, now Patent No. 3,641,128. Divided and this application June 25, 1971, Ser. No. 157,037

Int. Cl. A61k 27/00 US. Cl. 424319 2 Claims ABSTRACT OF THE DISCLOSURE The compound 4-(a-amino lower alkyl)bicyclo-[2,2,2]- octane-l-carboxylic acid and the pharmaceutically acceptable salts thereof are useful as anti-fibrinolytic compounds.

This application is a division of US. Ser. No. 834,138, filed June 17, 1969, which was issued as Pat. No. 3,641,- 128 on Feb. 8, 1972.

This invention relates to a new anti-fibrinolytic compound and to a method of counteracting certain hemorrhagic conditions and other disorders resulting from a pathological fibrinolytic state in patients. More specifically, this invention relates to a new compound of the structure a Email-QC 0 on wherein R is lower alkyl and the 'pharmaceutically acceptable salts thereof. More specifically, it relates to the prevention or treatment of a pathological fibrinolytic state in patients by the oral administration of from 1 to 20 and preferably 2 to 8 mg./kg. of body weight per day of the above compounds for varying periods of treatment.

The dissolution of fibrin deposits in mammals is due to their lysis by the enzyme plasmin (fibrinolysin) which is formed in the blood from plasminogen, also present in the blood. This conversion from plasminogen to plasmin is promoted by activators in the blood and it would appear that excessive fibrinolytic activity results from an over-abundance of such activators. When too much plasmin is present, the clotting system of the blood becomes unbalanced, viable clots cannot be maintained, and hemorrhage may result. This situation is known as a fibinolytic state. Other enzyme systems (i.e., the kallikreins, complement) may also be activated in an undesirable manner when such a state exists.

An interest has recently developed in anti-fibrinolytic agents, i.e. drugs which will inhibit the activation of plasminogen to form plasmin. These anti-fibrinolytic agents are believed to interfere with the function of the activators of converting plasminogen to plasmin. The clinical uses of such drugs include their administration to persons undergoing various kinds of surgery (such as heart-lung and prostate surgery), obsterical hemorrhage problems, menorrhagia, and many other uses which have been suggested in the literature (e.g. see Nilssen, Acta Medica Scand. Suppl. 448, volume 180, 1966).

A standard anti-fibrinolytic agent, against which newer ones are generally tested and compared is epsilon aminocaproic acid, known as EACA. One deficiency of this agent has been the very high dosages needed; in some cases 3-6 grams or more every 4 to 6 hours. Also, side eifects such as dizziness, nausea and diarrhea have been observed. More recently, two more potent agents have been described, namely trans-4-arninomethylcyclohexane carboxylic acid (AMCHA) and 4-aminomethylbenzoic acid (PAMBA). Each is reported to be more active than EACA by both in vitro and in vivo tests (e.g. see Anders- 3,767,814 Patented Oct. 23, 1973 sen et al. Scand. J. Haemat. (1965) 2, 230 and Melander et a1. Acta Pharmacol. et Toxicol 22, 340 (1965 both of which discuss AMCHA).

I have found a new class of aminomethyl bicyclic carboxylic acids which show an activity of about 50 times that of EACA in tests essentially the same as those known to correlate with clinical results. I have thus also found an improved anti-fibrinolytic method of therapeutic treatment requiring much smaller doses of the drug.

The new compound of my invention has the general wherein R is lower alkyl. The compound can be used as the racemate or either the d or Z isomer. The pharmaceutically acceptable salts of the compound also show anti-fibrinolytic activity.

The present invention also provides a process of preparing a compound of the structure which comprises the catalytic hydrogenation of a com pound of the structure wherein R is lower alkyl. The hydrogenation is carried out under conventional conditions generally in the presence of a catalyst such as platinum. In a preferred embodiment of the present invention, the lower alkyl group R of l to 5 carbon atoms, is either methyl or ethyl.

The compound is used in the method of this invention by either oral or intravenous administration, although the oral route is preferred. The esters and amides of this class compound are not themselves very active in vitro but the action of enzymes in vivo cause the slow liberation of the highly active amino acids, thus providing a prolonged availability of the drug in the body. This is important because of the tendency of these drugs to be swiftly eliminated in the urine. Such amides and esters are to be considered as being within the scope of the present invention since it is actually the present compound which produces the result Within the body.

The compound of this invention can be used in a composition comprising any pharmaceutically acceptable wrrier, in the form of pills, tablets or capsules. The pharmaceutically acceptable salts (both of the amino group such as the hydrochloride, hydrobromide, sulfate, citrate, tartrate, etc.and of the carboxy groupsuch as the alkali metal, alkaline earth metal, etc., salts) are readily usable, especially in injectable compositions.

The invention can be illustrated by the following eX- amples.

EXAMPLE 1 Racemic 4- (ct-aminoethyl)-bicyc1o-[2.2.2]-octane-1- carboxylic acid (A) 4-carbomethoxybicyclo [2.2.2]-oct-2-ene-1-carboxylic acid chloride.-A solution of 5.0 g. (0.024 moles) methyl hydrogenbicyclo [2.2.2]-oct 2-ene-1,4-dicarboxylate [F. W. Baker and L. M. Stock, J. Org. Chem. 32, 3344 (1967)] in 20 ml. of thionyl chloride is heated to reflux for 3 hours. After removal of the excess thionyl chloride by distillation in vacuo at steam bath temperatures and then reevaporation with 3-20 ml. portions of hexane, the resulting liquid is distilled in vacuo, giving 5.3 g. (97%) of a colorless liquid, B.P. 97-98 C./7.0 mm. Hg.

(B) 4-acetylbicyclo-[2.2.2] oct-Z-ene-l carboxylic acid.A mixture of 0.42 g. (0.017 mole) magnesium turnings, 2 ml. dry benzene and 0.1 ml. absolute ethanol is heated to reflux until the dissolution of magnesium begins. To this is added, over 30 minutes, a mixture of 2.72 g. (0.017 mole) diethyl malonate, 0.7 ml. absolute ethanol and 3 ml. benzene. After 3 hours of reflux, all of the magnesium has dissolved. The ethanol is then removed by azeotropic distillation with fresh portions of benzene, the volume brought to about ml. with benzene, and a solution of 3.43 g. (0.015 mole) 4-carbomethoxybicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid chloride in 5 ml. benzene is added at reflux over a 30 minute period. After an additional 3- /2 hours at reflux, the viscous mixture is poured into 100 ml. ice water and 50 ml. of 6 N hydrochloric acid. The combined benzene extracts, after washing with water and drying over MgSO gives 4.5 g. of a colorless liquid, an infrared spectrum of which exhibited no acid chloride absorption. The triester is hydrolyzed directly without purification by refluxing for 16 hours with a mixture of 25 ml. glacial acetic acid and 25 ml. concentrated hydrochloric acid. Evaporation leaves 1.83 g. (63% crude) of a white solid, which is chromatographed on silica gel (CHCl eluant) to remove a minor slower moving impurity. The chromatographed material is recrystallized from benzene-hexane, giving a white crystalline solid, M.P. 165.5168 C.

(C) 4-(m-oximinoethyl) bicyclo-[2.2.2]-oct-2-ene1- carboxylic acid.A mixture of 0.52 g. (7.5 mmoles) hydroxylarnine hydrochloride, 3 ml. absolute ethanol and 3 ml. pyridine is refluxed on a steam bath for 5 minutes. To this is added 0.49 g. (2.5 mmoles) 4-acetylbicyclo- [2.2.2]-oct-2-ene-1-carboxylic acid. After 3 hours at reflux, most of the solvent is removed in vacuo, then the residue is stirred with 30 ml. cold 3 N hydrochloric acid. The resulting crystalline solid is collected, Washed with water and air-dried. Weight: 0.44 g. (85%) MP. 242- 245 C. The material is recrystallized from 95% ethanol or ethyl acetate, M.P. 245247 C.

(D) dl-4-(u-aminoethyl bicyclo-[2.2.21-octane-1-carboxylic acid hydrochloride.To a solution of 270 mg. (1.29 mrnoles) 4-(u-oximinoethyD-bicyclo-[2.2.21-oct- 2-ene-l-carboxylic acid in 50 ml. 90% ethanol is added 0.5 ml. 6.0 N hydrochloric acid and 50 mg. platinum oxide. The mixture is shaken in a Parr hydrogenation apparatus at 30 lbs/in. and 25 C. for 3 hours. Filtra- 4 tion and evaporation leaves a white solid, which is recrystallized from ethanol-ether. Yield: 240 mg. The material, which is not noticeably hygroscopic, is purified by recrystallization from ethanol-ether and dried for analysis at C. in vacuo, M.P. 313.5315 C. dec.

EXAMPLE 2 The compound is tested in vitro by measuring the efiect of the inhibitor at various concentrations on the lysis times of a fibrin clot with a constant concentration of streptokinase in plasminogen-rich plasma. The concentration of the inhibitor which increases the geometric mean lysis time by 50% is estimated. Epsilon amino caproic acid (EACA) is used as a standard and the relative potencies are obtained, with the following results:

Relative in vitro activity Compound: (Weight basis) (A) Reference compound, EACA 1.0

(B) New compound, 4-(ot-aminoethyl)bicyclol2.2.2]-octane-l-carboxylic acid 50 wherein R is lower alkyl, and the pharmaceutically accepable salts thereof.

2. The method of claim 1 in which said daily administration is from 2 to 8 mg./ kg. of body weight.

References Cited OTHER REFERENCES Chem. Abst., Seventh Collective Index, vol. 56-65 (1962-1965), p. 93038.

SAM ROSEN, Primary Examiner 

